Acyl coenzyme A cholesterol acyltransferase (ACAT) is an enzyme for the synthesis of cholesterol ester from cholesterol and plays an important role in the metabolism of cholesterol and its absorption in digestive organs. Although many of conventional ACAT inhibitors serving as a therapeutic agent for hyperlipidemia or arteriosclerosis have acted on the ACAT in the small intestine or liver to lower plasma cholesterol level, they disadvantageously have side effects such as intestinal bleeding, intestinal disorder, diarrhea and liver disorder.
According to the recent studies, foamed macrophage is observed in a lesion of atherosclerosis. It has been revealed that the formation of macrophage-derived form cells is closely related to the progress of the lesion. Suppression of the formation of macrophage-derived form cells is expected to lead to the involution of an arteriosclerotic lesion itself. At the arteriosclerotic lesion site, the activity of ACAT in the artery wall has been elevated and cholesterol ester has accumulated on the artery wall so that it is presumed that the ACAT activity in the artery wall has a close relation to arteriosclerosis (Exp. Mol. Pathol., 44, 329–339 (1986)). Accordingly, the inhibition of the ACAT activity in the artery wall can suppress conversion from free cholesterol to cholesterol ester by ACAT. On the other hand, free cholesterol in the cells can be eliminated from the cells by high density lipoprotein (HDL) and conveyed to the liver (reverse transfer by HDL). The free cholesterol in the liver can be metabolized so that accumulation of cholesterol ester at the arteriosclerotic lesion site is expected to be suppressed (Biochim. Biophys. Acta. 2001 15, 1530(1): 111–122).
An agent which inhibits ACAT in the artery wall is thus considered to become a direct remedy for arteriosclerosis and there is accordingly a demand for the exploitation of such a medicine.
Under such situations, finding that cyclic diamine compounds represented by the following formula (A):
wherein, Ar represents an aryl group which may be optionally substituted,
represents a divalent residue of benzene, pyridine, cyclohexane or naphthalene which may be optionally substituted, X represents NH, an oxygen atom or a sulfur atom, Y represents a sulfur atom or the like, Z represents a single bond or the like, 1 stands for an integer of from 1 to 15, m stands for an integer of 2 or 3 and n stands for an integer of from 1 to 3, or salts thereof, or solvates of these compounds strongly inhibit ACAT in the artery wall and will be a preventive or remedy for arteriosclerosis with less side effects, the present inventors filed a patent application for it (International Publication No. 98/54153). Moreover, the present inventors found that among the compounds represented by the above-described formula (A), the below-described compound (B), salts thereof or solvates thereof have an excellent action as an artery wall-selective ACAT inhibitor and are excellent in oral absorption, and filed a patent application for it (International Publication No. 03/018564).

However, in the in vitro human liver microsome test, Compound (B) was revealed to show low metabolic resistance. Accordingly, there is a demand for ACAT inhibitors capable of strongly inhibiting ACAT in the artery wall as well as having high metabolic resistance.